Graduate Thesis Or Dissertation

 

Drug Discovery from Diverse Bacteria – Bioactivity-guided Isolation of Known and New Metabolites Public Deposited

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/sb397f92n

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  • Exploring bioactive natural products has contributed largely to clinically approved drugs we have been using over the last 100 years. Especially among the anti-infective drugs, around 70% of currently used antibiotics were discovered or derived from microbial secondary metabolites, among them compounds like vancomycin, chloramphenicol, and erythromycin. Facing the unavoidable fact of microbial drug resistance and low cure rate of cancers, exploring new drug leads is essential and urgent. Drug discovery from microbial sources has just scratched the surface: recent surveys have shown that bacterial genomes are filled with genes encoding for secondary metabolites, that have not been seen in the laboratory, and that unique environments and underexplored biodiverse niches can yield new bacterial species with unique chemotypes. Bioactivity-guided isolation with dereplication is still an efficient method used in the laboratory to discover new bioactive compounds. This thesis includes the details on isolation of bacterial strains from diverse environments, bioactivity-guided fractionation, and dereplication/characterization of isolated metabolites. Bacterial strain library, consisting ~400 bacteria, was established in Loesgen Lab. The protocols of bacterial isolation from terrestrial and marine sources, the workflow of methods for chemical and bioactivity screening, and dereplication methods are presented. Approximately 50% of the bacterial strains have been extracted, fractionated and tested for cytotoxicity against a colon cancer cell line. Projects were prioritized based on the chemical and bioactivity screening results. An investigation of 19 bacterial strains from Oregonian soils yielded twelve known metabolites and two new natural products, a new tetrapeptide from Streptomyces sp. and a new chromone from Paraburkholderia sp. Their absolute configuration was established via advanced Marfey’s analysis and X-ray crystallography. Besides, an unusual cytotoxic diterpenoid was discovered from Streptomyces flaveolus, featuring five chiral centers and two double bond geometries within a fused bicyclo[8.4.0]tetradecane macrocycle. The metabolite existed in two distinct ring-flipped conformers in solution and its absolute configuration was determined by Mosher ester analysis, J-based coupling analysis, and DFT modeling.
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  • Pending Publication
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  • 2019-12-12 to 2021-01-12

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